This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dr. Voyich has investigated the role of the SaeR/S two-component system (TCS) in USA300, a prominant circulating clone of community-associated methicillin resistant (CA-MRSA) Staphylococcus aureus. Using an saeR/S isogenic deletion mutant of USA300 (USA300[unreadable]saeR/S) in murine models of sepsis and soft tissue infection, Dr. Voyich has demonstrated this sensory system is critical to USA300 pathogenesis during both superficial and invasive infection. Oligonucleotide microarray and real time RT-PCR identified numerous extracellular virulence genes downregulated in USA300[unreadable]saeR/S involved with host cell lysis, manipulation of the host immune response, and adhesion to host proteins. 5'-RACE analysis identified an SaeR recognition sequence (SRS) specific to gene promoters strongly influenced by SaeR/S, and gel shifts demonstrated the binding of purified recombinant SaeR to promoter sequences corresponded to the number of SRSs within that sequence. This investigation reveals SaeR/S directly interacts with a conserved consensus sequence within specific virulence gene promoters to substantially influence the pathogenesis of USA300.